The 5-lipoxygenase inhibitor tepoxalin induces oxidative damage and altered PTEN status prior to apoptosis in canine osteosarcoma cell lines.

Autor: Loftus JP; Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA., Cavatorta D; Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA., Bushey JJ; Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA., Levine CB; Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA., Sevier CS; Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY, USA., Wakshlag JJ; Department of Clinical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, USA.
Jazyk: angličtina
Zdroj: Veterinary and comparative oncology [Vet Comp Oncol] 2016 Jun; Vol. 14 (2), pp. e17-30. Date of Electronic Publication: 2014 May 12.
DOI: 10.1111/vco.12094
Abstrakt: The 5-lipoxygenase (5-LOX) inhibitor tepoxalin has been shown to slow canine osteosarcoma (OSA) tumour xenografts growth, yet the mechanisms are poorly elucidated. Further examination of tepoxalin in canine OSA cell lines shows that tepoxalin treated cells undergo apoptosis through caspase-3 activation and annexin staining. Interestingly, apoptosis is superseded by an increase in reactive oxygen species (ROS), as measured by activation of dihydrorhodamine 123 and mitosox. This increase in ROS appears to be related to the 5-LOX inhibitor regardless of cellular 5-LOX status, and was not observed after treatment with the tepoxalin metabolite RWJ20142. Additionally, 5-LOX inhibition by tepoxalin appears to increase phosphatase and tensin (PTEN) homolog activity by preventing its alkylation or oxidation. PTEN modification or inhibition allows phosphoinositide-3 (PI3) kinase activity thereby heightening activation of protein kinase B (AKT) phosphorylation. Our data suggest that off target oxidation and LOX inhibition play roles in the apoptotic response.
(© 2014 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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